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Fürst, R.* ; Schroeder, T. ; Eilken, H.M. ; Bubik, M.F.* ; Kiemer, A.K.* ; Zahler, S.* ; Vollmar, A.M.*

MAPK phosphatase-1 represents a novel anti-inflammatory target of glucocorticoids in the human endothelium.

FASEB J. 21, 74-80 (2007)
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Glucocorticoids are well-established anti-inflammatory drugs thought to mainly act by inhibition of proinflammatory transcription factors like NF-{kappa}B. In recent years, however, transcription factor-independent mechanisms of glucocorticoid action have been proposed, namely the influence on MAPK pathways. Here we identify MAPK phosphatase-1 (MKP-1) as a pivotal mediator of the anti-inflammatory action of glucocorticoids in the human endothelium. We applied dexamethasone (Dex) to TNF-{alpha}-activated human endothelial cells and used the adhesion molecule E-selectin as inflammatory read-out parameter. Dex is known to reduce the expression of E-selectin, which is largely regulated by NF-{kappa}B. Here, we communicate that Dex at low concentrations (1–100 nM) markedly attenuates E-selectin expression without affecting NF-{kappa}B. Importantly, Dex is able to increase the expression of MKP-1, which causes an inactivation of TNF-{alpha}-induced p38 MAPK and mediates inhibition of E-selectin expression. In endothelial MKP-1–/– cells differentiated from MKP-1–/– embryonic stem cells and in MKP-1-silenced human endothelial cells, Dex did not inhibit TNF-{alpha}-evoked E-selectin expression. Thus, our findings introduce MKP-1 as a novel and crucial mediator of the anti-inflammatory action of glucocorticoids at low concentrations in the human endothelium and highlight MKP-1 as an important and promising anti-inflammatory drug target.—Fürst, R., Schroeder, T., Eilken, H. M., Bubik, M. F., Kiemer, A. K., Stefan Zahler, S., Vollmar, A. M. MAPK phosphatase-1 represents a novel anti-inflammatory target of glucocorticoids in the human endothelium
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords inflammation
ISSN (print) / ISBN 0892-6638
e-ISSN 1530-6860
Journal FASEB Journal
Quellenangaben Volume: 21, Issue: 1, Pages: 74-80 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place Bethesda, Md.
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Stem Cell Research (ISF)